Regional hyperthermia combined with radiotherapy for locally advanced non-small cell lung cancers: a multi-institutional prospective randomized trial of the International Atomic Energy Agency

Background An International Atomic Energy Agency (IAEA)-sponsored, multi-institutional prospective randomized trial was conducted to clarify whether the combination of hyperthermia and radiotherapy improves the local response rate of locally advanced non-small cell lung cancer (NSCLC) compared with that obtained by radiotherapy alone. Methods Between October 1998 and April 2002, 80 patients with locally advanced NSCLC were randomized to receive either standard radiation therapy alone (RT) or radiation therapy combined with hyperthermia (RT + HT). The primary endpoint was the local response rate. The secondary endpoints were local progression-free survival and overall survival. Results The median follow-up period was 204 days for all patients and 450 days for surviving patients. There were no significant differences between the two arms with regard to local response rate (P = 0.49) or overall survival rate (P = 0.868). However, local progression-free survival was significantly better in the RT+HT arm (P = 0.036). Toxicity was generally mild and no grade 3 late toxicity was observed in either arm. Conclusion Although improvement of local progression-free survival was observed in the RT+HT arm, this prospective randomized study failed to show any substantial benefit from the addition of hyperthermia to radiotherapy in the treatment of locally advanced NSCLC.     

Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group.

PURPOSE: This phase III study compared overall survival in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) when treated with single-agent gemcitabine versus gemcitabine/carboplatin. Secondary objectives were to compare response, time to progression, toxicity, and quality of life. PATIENTS AND METHODS: Chemotherapy-naive patients received either gemcitabine alone (1,250 mg/m2 on days 1 and 8; gemcitabine arm) or with carboplatin (area under the curve 5 on day 1; GC arm) every 21 days. RESULTS: Demographics and disease characteristics of 334 randomly assigned patients were comparable on both arms. An intent-to-treat analysis showed significantly better overall survival (log-rank P = .0205) and 2-year survival (15% v 5%; P = .009) favoring the GC arm. Per Cox multivariate analysis, only two covariates, treatment arm (GC v G) and baseline performance status (0 or 1 v 2), independently influenced survival. Per-protocol analyses showed significantly longer median time to progression (5.7 v 3.9 months; P = .0001) and significantly higher objective response rate (29.6 v 11.3%; P < .0001) in the GC arm. Grade 3 to 4 leucopenia and thrombocytopenia were significantly more pronounced in the GC arm (P for both variables < .001) but importantly without associated increases in fever, infection, bleeding, or hospitalizations. There was no discernible difference in global quality-of-life patterns between treatment arms. CONCLUSION: In advanced NSCLC, gemcitabine/carboplatin therapy resulted in significant survival benefit compared with single-agent gemcitabine without undue increase in toxicity.     

A randomised phase III study of palliative radiation with concomitant carboplatin for brain metastases from non-small cell carcinoma of the lung

PURPOSE: To determine if the addition of carboplatin chemotherapy to whole brain irradiation improves response and survival in patients with brain metastases from non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-two patients with brain metastases from NSCLC and performance status ECOG 0-2 were randomised to receive either whole brain radiotherapy (WBRT) alone (20Gy in five fractions) or the same radiotherapy plus concomitant carboplatin (70 mg/m(2) intravenously for 5 days). RESULTS: The median survival was 4.4 months in the radiotherapy alone (RT) arm and 3.7 months in the combined treatment (RTC) arm (P = 0.64). The objective response rates of 10% on the RT arm and 29% on the RTC arm were not significantly different (P = 0.24). The trial was closed early because of poor accrual. CONCLUSIONS: Although no firm conclusions can be made regarding the efficacy of the combined treatment, this prospective study highlights the poor objective response rates and relatively poor symptom control despite standard treatment of brain metastases from NSCLC.     

Combined modality treatment for locally advanced non-small cell lung cancer: preoperative chemoradiation does not result in a poorer quality of life

The German Lung Cancer Cooperative Group (GLCCG) is assessing the impact of chemoradiation in addition to chemotherapy in the neoadjuvant treatment of stage III NSCLC. After three cycles of cisplatin/etoposide patients receive either hyperfractionated radiotherapy (RT) with concurrent carboplatin/vindesine and then surgery (arm A) versus surgery and then conventional RT (arm B). Quality of life (QL) was assessed throughout therapy using the EORTC QLQ-C30 and EORTC QLQ-LC 13. Of 126 eligible patients, 54 completed treatment. For patients in both treatment arms physical functioning decreased, whereas dyspnoea, fatigue and pain increased from beginning to the end of treatment. For self-assessed QL no statistically significant effect was found in or between the two treatment arms. The combined modality approach with preoperative radio/chemotherapy proves to be feasible in treating locally advanced NSCLC patients without decreasing their subjective QL.     

Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma.

PURPOSE: We report the 5-year survival and late toxicity results of a randomized clinical trial, which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma, using concomitant radiochemotherapy (arm B), compared with standard radiotherapy (arm A). PATIENTS AND METHODS: A total of 226 patients were entered onto a phase III multicenter randomized trial comparing radiotherapy alone (70 Gy in 35 fractions; arm A) with concomitant radiochemotherapy (70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil; arm B). Prognostic factors were evaluated by univariate and multivariate analysis. Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity, hearing, taste, mandibula, and teeth damage, and Radiation Therapy Oncology Group toxicity criteria for skin, salivary gland, and mucosa. RESULTS: Five-year overall survival, specific disease-free survival, and locoregional control rates were 22% and 16% (log-rank P =.05), 27% and 15% (P =.01), and 48% and 25% (P =.002), in arm B and arm A, respectively. Stage IV, hemoglobin level lower than 125 g/L, and standard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis. One or more grade 3 to 4 complications occurred in 56% of the patients in arm B, compared with 30% in arm A (P was not significant). CONCLUSION: Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity. Anemia was the most important prognostic factor for survival in both arms.     

Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial.

BACKGROUND: The combination of paclitaxel with cisplatin or carboplatin has significant activity in non-small-cell lung cancer (NSCLC). This phase III study of chemotherapy-na?ve advanced NSCLC patients was designed to assess whether response rate in patients receiving a paclitaxel/carboplatin combination was similar to that in patients receiving a paclitaxel/cisplatin combination. Paclitaxel was given at a dose of 200 mg/m(2) (3-h intravenous infusion) followed by either carboplatin at an AUC of 6 or cisplatin at a dose of 80 mg/m(2), all repeated every 3 weeks. Survival, toxicity and quality of life were also compared. PATIENTS AND METHODS: Patients were randomised to receive one of the two combinations, stratified according to centre, performance status, disease stage and histology. The primary analyses of response rate and survival were carried out on response-evaluable patients. Survival was also analysed for all randomised patients. Toxicity analyses were carried out on all treated patients. RESULTS: A total of 618 patients were randomised. The two treatment arms were well balanced with regard to gender (83% male), age (median 58 years), performance status (83% ECOG 0-1), stage (68% IV, 32% IIIB) and histology (38% squamous cell carcinoma). In the paclitaxel/carboplatin arm, 306 patients received a total of 1311 courses (median four courses, range 1-10 courses) while in the paclitaxel/cisplatin arm, 302 patients received a total of 1321 courses (median four courses, range 1-10 courses). In only 76% of courses, carboplatin was administered as planned at an AUC of 6, while in 96% of courses, cisplatin was given at the planned dose of 80 mg/m(2). The response rate was 25% (70 of 279) in the paclitaxel/carboplatin arm and 28% (80 of 284) in the paclitaxel/cisplatin arm (P = 0.45). Responses were reviewed by an independent radiological committee. For all randomised patients, median survival was 8.5 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm [hazard ratio 1.20, 90% confidence interval (CI) 1.03-1.40]; the 1-year survival rates were 33% and 38%, respectively. On the same dataset, a survival update after 22 months of additional follow-up yielded a median survival of 8.2 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm (hazard ratio 1.22, 90% CI 1.06-1.40; P = 0.019); the 2-year survival rates were 9% and 15%, respectively. Excluding neutropenia and thrombocytopenia, which were more frequent in the paclitaxel/carboplatin arm, and nausea/vomiting and nephrotoxicity, which were more frequent in the paclitaxel/cisplatin arm, the rate of severe toxicities was generally low and comparable between the two arms. Overall quality of life (EORTC QLQ-C30 and LC-13) was also similar between the two arms. CONCLUSIONS: This is the first trial comparing carboplatin and cisplatin in the treatment of advanced NSCLC. Although paclitaxel/carboplatin yielded a similar response rate, the significantly longer median survival obtained with paclitaxel/cisplatin indicates that cisplatin-based chemotherapy should be the first treatment option.     

Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer.

PURPOSE: To compare four cycles of therapy versus continuous therapy to determine the optimal duration of chemotherapy in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Stage IIIB/IV NSCLC patients were randomized to arm A (four cycles of carboplatin at an area under the curve of 6 and paclitaxel 200 mg/m(2) every 21 days) or arm B (continuous treatment with carboplatin/paclitaxel until progression). At progression, all patients on both arms were to receive second-line weekly paclitaxel at 80 mg/m(2)/wk. The primary end points were survival and quality of life (QOL). RESULTS: Two hundred thirty patients were randomized. Fifty-seven percent of arm A patients completed four courses of therapy. In the 116 arm B patients, the median number of cycles delivered was four (range, zero to 19 cycles). Forty-two percent received five or more cycles; 18% received eight or more cycles. Overall response rates were 22% and 24% for arms A and B, respectively (P =.80). Median survival time and 1-year survival rates were 6.6 months and 28% for arm A and 8.5 months and 34% for arm B, respectively (log-rank P =.63). Rates of hematologic and nonhematologic toxicity were similar between the two arms, except for neuropathy. The rate of grade 2 to 4 neuropathy increased from 19.9% (95% confidence interval [CI], 13.6% to 26.2%) at cycle 4 to 43% (95% CI, 28.6% to 57.4%) at cycle 8. There were no differences in QOL. Only 45% of patients received second-line therapy (42% in arm A v 47% in arm B, P =.42). CONCLUSION: This study shows no overall benefit in survival, response rates, or QOL to continuing treatment with carboplatin/paclitaxel beyond four cycles in advanced NSCLC.     

Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol.

PURPOSE: This phase II noncomparative randomized trial was conducted to determine the optimal sequencing and integration of paclitaxel/carboplatin with standard daily thoracic radiation therapy (TRT), in patients with locally advanced unresected stage III non-small-cell lung cancer (NSCLC). Survival data were compared with historical standard sequential chemoradiotherapy data from the Radiation Therapy Oncology Group. PATIENTS AND METHODS: Patients with unresected stages IIIA and IIIB NSCLC, with Karnofsky performance status > or = 70% and weight loss < or = 10%, received two cycles of induction paclitaxel (200 mg/m2)/carboplatin (area under the plasma concentration time curve [AUC] = 6) followed by TRT 63.0 Gy (arm 1, sequential) or two cycles of induction paclitaxel (200 mg/m2)/carboplatin (AUC = 6) followed by weekly paclitaxel (45 mg/m2)/carboplatin (AUC = 2) with concurrent TRT 63.0 Gy (arm 2, induction/concurrent), or weekly paclitaxel (45 mg/m2)/carboplatin (AUC = 2)/TRT (63.0 Gy) followed by two cycles of paclitaxel (200 mg/m2)/carboplatin (AUC = 6; arm 3, concurrent/consolidation). RESULTS: With a median follow-up time of 39.6 months, median overall survival was 13.0, 12.7, and 16.3 months for arms 1, 2, and 3, respectively. During induction chemotherapy, grade 3/4 granulocytopenia occurred in 32% and 38% of patients on study arms 1 and 2, respectively. The most common locoregional grade 3/4 toxicity during and after TRT was esophagitis, which was more pronounced with the administration of concurrent chemoradiotherapy on study arms 2 and 3 (19% and 28%, respectively). CONCLUSION: Concurrent weekly paclitaxel, carboplatin, and TRT followed by consolidation seems to be associated with the best outcome, although this schedule was associated with greater toxicity.     

Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non-small-cell lung cancer.

PURPOSE: Greater toxicities have been recognized to be a consequence of combined chemotherapy and radiotherapy in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This study was designed to determine if the use of amifostine could reduce treatment-related toxicities associated with the use of paclitaxel plus carboplatin and thoracic radiotherapy. PATIENTS AND METHODS: Sixty patients with unresectable stage III NSCLC were treated with two cycles of paclitaxel 175 mg/m2 and carboplatin (area under the time-concentration curve = 6), followed by thoracic radiotherapy (64 Gy) with concurrent weekly paclitaxel 60 mg/m2. Patients were randomly assigned to receive 740 mg/m2 of amifostine (arm A) or placebo (arm B) before each dose of paclitaxel and carboplatin. Treatment-related toxicities were evaluated at each visit and nerve conduction tests were performed before and after treatment for the objective assessment of neurotoxicity. RESULTS: There was no significant difference between arms A and B in grade 3 to 4 neutropenia. In all 72 neurophysiological parameters measured, there was no significant difference between the two treatment arms, although there was a trend toward fewer patients showing deterioration in arm A for six of the parameters. Grade 2 to 3 esophagitis occurred in 43% of patients in arm A and in 70% of patients in arm B. The difference of -27% (95% confidence limit = -50%, 0.4%) was not statistically significant. Response rates and survival were also not significantly different between the two arms. CONCLUSION: Pretreatment with amifostine showed a trend toward reducing the severity of esophagitis associated with concurrent chemoradiotherapy, but it did not reach statistical significance. There was no significant protective effect on hematologic or neurologic toxicities induced by paclitaxel and carboplatin.     

Functional polymorphisms of the microsomal epoxide hydrolase gene: a reappraisal on a early-onset lung cancer patients series

As concomitant chemoradiotherapy for stage III NSCLC is associated with survival advantage in comparison to a sequential approach, we conducted a phase III randomised study aiming to determine the best sequence and safety of chemotherapy (CT) and chemoradiotherapy (CT-RT), using a regimen with cisplatin (CDDP), gemcitabine (GEM) and vinorelbine (VNR). Unresectable stage III NSCLC patients received CDDP (60 mg/m(2)), GEM (1g/m(2), days 1 and 8) and VNR (25mg/m(2), days 1 and 8) with reduced dosage of GEM and VNR during radiotherapy (66Gy). Two cycles of CT with radiotherapy followed by two further cycles of CT alone were administered in arm A or the reverse sequence in arm B. The study was prematurely closed for poor accrual due to administrative problems. Forty-nine eligible patients were randomised. Response rates and median survival times were, respectively 57% (95% CI: 36-78%) and 17 months (95% CI: 9.3-24.6 months) in arm A and 79% (95% CI: 64-94%) and 23.9 months (95% CI: 13.3-34.5 months) in arm B (p>0.05). Chemotherapy dose-intensity was significantly reduced in arm A. Grade 3-4 oesophagitis occurred in 5 patients. One case of grade 5 radiation pneumonitis was observed. In conclusion, chemoradiotherapy with CDDP, GEM and VNR appears feasible as initial treatment or after induction chemotherapy. Consolidation chemoradiotherapy seems less toxic with a better observed response rates and survival although no valid conclusion can be drawn from the comparison of both arms.     

Randomized, multicenter, open-label phase II study of gemcitabine plus single-dose versus split-dose carboplatin in the treatment of patients with advanced-stage non-small-cell lung cancer

BACKGROUND: Gemcitabine/carboplatin is a convenient and effective treatment for advanced-stage non-small-cell lung cancer (NSCLC), but modification of the schedule to diminish thrombocytopenia is worthwhile. PATIENTS AND METHODS: One hundred fifty-eight chemotherapy-naive patients with stage IIIB/IV NSCLC were randomized from 15 centers in Germany to receive gemcitabine 1250 mg/m(2) on days 1 and 8 plus carboplatin area under the curve 5 on day 1 (arm A) or carboplatin area under the curve 2.5 on days 1 and 8 (arm B), every 21 days for 4 cycles. RESULTS: The 2 arms (A vs. B) were well balanced with regard to patient baseline characteristics: stage IV 72.5% versus 69%, median Eastern Cooperative Oncology Group performance status 1 versus 1. The incidence of grade 3/4 hematologic toxicity was as follows (percentage of patients in arm A vs. B): leukopenia 37.5% versus 27% (P = 0.075), granulocytopenia 36% versus 36%, and thrombocytopenia 51% versus 35% (P = 0.017). Nonhematologic toxicity was modest and comparable with both schedules. The overall response rate was 46% versus 36% (P = 0.12), and 24% versus 42% had stable disease. Median progression-free survival (5.8 months vs. 6.1 months) and overall survival (11.7 months vs. 10.7 months) were not significantly different between arms A and B. CONCLUSION: Splitting the dose of carboplatin between days 1 and 8 on the same days as gemcitabine results in a significantly decreased incidence of severe thrombocytopenia, without compromising the activity of the combination.     

Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma

BACKGROUND: We designed a randomized clinical trial to test whether the addition of three cycles of chemotherapy during standard radiation therapy would improve disease-free survival in patients with stages III and IV (i.e., advanced oropharynx carcinoma). METHODS: A total of 226 patients have been entered in a phase III multicenter, randomized trial comparing radiotherapy alone (arm A) with radiotherapy with concomitant chemotherapy (arm B). Radiotherapy was identical in the two arms, delivering, with conventional fractionation, 70 Gy in 35 fractions. In arm B, patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin (70 mg/m(2) per day) and 5-fluorouracil (600 mg/m(2) per day) by continuous infusion. The two arms were equally balanced with regard to age, sex, stage, performance status, histology, and primary tumor site. RESULTS: Radiotherapy compliance was similar in the two arms with respect to total dose, treatment duration, and treatment interruption. The rate of grades 3 and 4 mucositis was statistically significantly higher in arm B (71%; 95% confidence interval [CI] = 54%-85%) than in arm A (39%; 95% CI = 29%-56%). Skin toxicity was not different between the two arms. Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level. Three-year overall actuarial survival and disease-free survival rates were, respectively, 51% (95% CI = 39%-68%) versus 31% (95% CI = 18%-49%) and 42% (95% CI = 30%-57%) versus 20% (95% CI = 10%-33%) for patients treated with combined modality versus radiation therapy alone (P =.02 and.04, respectively). The locoregional control rate was improved in arm B (66%; 95% CI = 51%-78%) versus arm A (42%; 95% CI = 31%-56%). CONCLUSION: The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx.     

Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin

PURPOSE: The combination of paclitaxel with carboplatin is effective in advanced-stage non-small cell lung cancer (NSCLC). This phase III study was designed to compare the efficacy and tolerability of a weekly versus an every-3-week schedule in the first-line treatment of advanced-stage NSCLC. PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to receive paclitaxel 100 mg/m2 and carboplatin at an area under the curve of 2 once weekly for 6-8 weeks (arm A) or paclitaxel 200 mg/m2 and carboplatin at an area under the curve of 6 on day 1 every 21 days (arm B). RESULTS: A total of 883 patients received >or= 1 chemotherapy cycle and were included in the results. The objective response rates observed (complete response plus partial response) were 38% for arm A and 33% for arm B. Median times to progression and median survival times were 6.1 months and 8.9 months in arm A and 7.2 months and 9.5 months in arm B, respectively. There were no significant differences between treatment arms. The chemotherapy was well tolerated in both schedules. However, grade 3/4 sensory neuropathy occurred more frequently with the every-3-week schedule (9.1% vs. 4.4%), whereas grade 3/4 diarrhea occurred more frequently with the weekly schedule (4.2% vs. 1.1%). CONCLUSION: In terms of response and survival, paclitaxel/carboplatin administered once weekly is comparable with the every-3-week schedule. Toxicity differences should be considered when choosing the appropriate schedule for the individual.     

A randomised phase III study of accelerated or standard fraction radiotherapy with or without concurrent carboplatin in inoperable non-small cell lung cancer: final report of an Australian multi-centre trial.

PURPOSE: To investigate the effects separately and together of (a) shortening overall treatment time and (b) giving concurrent carboplatin in patients having radical radiotherapy for inoperable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between April 1989 and May 1995, 204 patients with medically inoperable or technically unresectable NSCLC localised to the primary site and regional lymph nodes were randomised to receive one of four treatments using a 2 x 2 factorial design: standard radiotherapy, 60 Gy in 30 fractions in 6 weeks (R6); accelerated radiotherapy, 60 Gy in 30 fractions in 3 weeks (R3); standard radiotherapy as in R6 with carboplatin 70 mg/m2/day for 5 days during weeks 1 and 5 of radiotherapy (R6C); accelerated radiotherapy as in R3 with carboplatin 70 mg/m2/day for 5 days during week 1 of radiotherapy (R3C). RESULTS: The estimated median survival of all randomised patients was 15.7 months and estimated 2-year survival was 31%. The longest survival was seen in patients randomised to R6C (median 20.3 months, 41% surviving at 2 years) but there were no statistically significant differences between treatment arms or treatment factors (carboplatin versus no carboplatin, accelerated versus conventional radiotherapy). Haematological toxicity was significantly greater in patients treated with carboplatin and oesophageal toxicity was significantly greater and more protracted in patients treated with accelerated radiotherapy. CONCLUSIONS: This study failed to show a significant survival advantage for any of the treatment arms or factors. Halving overall treatment time resulted in significantly greater oesophageal toxicity with no suggestion of a survival advantage.     

Induction chemotherapy plus high-dose radiotherapy versus radiotherapy alone in locally advanced unresectable non-small-cell lung cancer

Background: High-dose radiation therapy is generally recommendedas standard treatment in regionally advanced unresectable non-small-celllung cancer (NSCLC), but medianand long-term survival remainpoor. Some reports have recently shown an improvement of resultsin advanced NSCLC when cisplatin was included in the chemotherapyregimens. Therefore, we designed a randomized trial to determinewhether induction chemotherapy before high-dose radiotherapyimproves response rate and survival in stage HI NSCLC over thatachieved with radiotherapy alone. Patients and methods: From March, 1984 to December, 1988, 66consecutive patients with stage HI unresectable NSCLC were randomizedto one of two treatment arms; 61 were evaluable for survivaland 58 for response and toxicity. Patients randomly assignedto arm A received cisplatin (CDDP 100 mg/m² on day 1) and etoposide(VP 16 120 mg/ m² on days 1, 2, 3) every 3 wks for 3 coursesfollowed by radiotherapy 56 Gy on pre-treatment tumor volumeand 40 Gy on mediastinum and bilateral supraclavicular nodes.Patients assigned to arm B received only the same radiotherapy.The 61 eligible patients were comparable in terms of age, performancestatus, histology and treatment. Results: Response rate was 53% in arm A and 32% in arm B. Themedian survival was 52 wks for the combined treatment arm and36 wks for the radiation therapy arm. At six years of follow-upall the patients were dead. Toxicity was mild and no treatment-relateddeaths were recorded. Conclusion: Induction chemotherapy produced a better responserate and a trend of improved survival (4 months) but a significantsurvival advantage was not achieved (p < 0.11), probablybecause of the small number of patients enrolled in the trial. chemotherapy, non-small-cell lung cancer, radiotherapy, combined treatment     

Randomized Phase II Trial Comparing Chemoradiotherapy with Chemotherapy for Completely Resected Unsuspected N2-Positive Non–Small Cell Lung Cancer

IntroductionWe investigated whether concurrent chemoradiotherapy (CCRT) would increase survival in patients with completely resected unsuspected N2-positive NSCLC versus in patients who received adjuvant chemotherapy alone.MethodsEligible patients were randomly assigned (1:1) to either the CCRT arm or the chemotherapy arm. In the CCRT arm, patients received concurrent thoracic radiotherapy (50 Gy in 25 fractions) with five cycles of weekly paclitaxel (50 mg/m²) and cisplatin (25 mg/m²), followed by two additional cycles of paclitaxel (175 mg/m²) plus cisplatin (80 mg/m²) at 3-week intervals. In the chemotherapy arm, patients received four cycles of adjuvant paclitaxel (175 mg/m²) and carboplatin (area under the curve = 5.5) every 3 weeks. The primary end point was disease-free survival.ResultsWe enrolled and analyzed 101 patients (51 received CCRT and 50 received chemotherapy). In all, 74 and 27 patients were preoperatively staged as N0 and N1 diseases, respectively. The baseline characteristics were well balanced between the two arms. The median disease-free survival of the CCRT arm was 24.7 months, which was not significantly different from that of the chemotherapy arm (21.9 months) (hazard ratio = 0.94, 95% confident interval: 0.58–1.52, p = 0.40). There was no difference in overall survival (74.3 months in CCRT arm and 83.5 months in the chemotherapy arm) (hazard ratio = 1.33, 95% confident interval: 0.71–2.49).ConclusionsThere was no survival benefit from adjuvant CCRT compared with from platinum-based chemotherapy alone for completely resected unsuspected N2-positive NSCLC. However, the role of sequential radiotherapy administered after adjuvant chemotherapy is being evaluated, and further study is needed to evaluate the optimal radiotherapy approach for completely resected N2-positive NSCLC.     

Efficacy and safety analysis according to histology for S-1 in combination with carboplatin as first-line chemotherapy in patients with advanced non-small-cell lung cancer: updated results of the West Japan Oncology Group LETS study

BackgroundA phase III study (Lung Cancer Evaluation of TS-1) previously demonstrated noninferiority in terms of overall survival (OS) at interim analysis for carboplatin–S-1 compared with carboplatin–paclitaxel for first-line treatment of advanced non-small-cell lung cancer (NSCLC).Patients and methodsA total of 564 patients were randomly assigned to receive either carboplatin on day 1 plus oral S-1 on days 1–14 or carboplatin–paclitaxel on day 1 every 21 days. Updated results and post hoc subgroup analysis according to tumor histology are presented.ResultsThe updated analysis revealed a median OS of 15.2 months in the carboplatin–S-1 arm and 13.1 months in the carboplatin–paclitaxel arm, with a hazard ratio (HR) of 0.956 [95% confidence interval (CI) 0.793–1.151], consistent with the previous primary analysis. Median OS was 14.0 months in the carboplatin–S-1 arm and 10.6 months in the carboplatin–paclitaxel arm (HR 0.713; 95% CI 0.476–1.068) for patients with squamous cell carcinoma (SCC), with corresponding values of 15.5 and 13.9 months (HR 1.060; 95% CI 0.859–1.308) for those with non-SCC.ConclusionsThese results establish the efficacy and safety of carboplatin–S-1 in patients with advanced NSCLC regardless of tumor histology.     

局部晚期非小细胞肺癌同步放化疗并序贯化疗与单纯序贯放化疗的对比研究

目的 观察局部晚期非小细胞肺癌（NSCLC）接受调强放疗（IMRT）联合同步吉西他滨和卡铂方案（GC）化疗与序贯放化疗的近、远期疗效和不良反应。方法 回顾性分析不能进行手术治疗和拒绝手术治疗的局部晚期NSCLC患者65例,其中同步放化疗并序贯化疗组给予IMRT同步联合GC治疗者32例,单纯序贯放化疗组为33例给予IMRT后序贯GC治疗。通过统计分析比较两组之间的近期有效率、远期生存率和不良反应。结果 两组均完成治疗,随访率100%,同步放化疗并序贯化疗组近期有效率为75%,单纯序贯放化疗组为66.7% ,两组比较差异有统计学意义（P＜0.05）。两组1、3年生存率相比较,同步放化疗并序贯化疗组为68. 2% 、20. 5% ;单纯序贯放化疗组为 50. 1% 、11.3%;同步放化疗并序贯化疗组明显优于单纯序贯放化疗组（P＜0.05）。两组不良反应情况对比,差异无统计学意义（P＞0.05）。结论 IMRT同步联合GC方案并序贯化疗治疗局部晚期NSCLC,可以提高患者的远期生存率且不良反应可耐受。     

Phase II study of gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer

Purpose To evaluate the efficacy and safety of gemcitabine in combination with carboplatin at standard rate or fixed dose rate infusion in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods In this prospective study, patients with chemonaive advanced NSCLC were randomized to receive gemcitabine at a standard rate (gemcitabine 1,200 mg/m² over 30 min, the standard arm) or a fixed dose rate (gemcitabine 1,200 mg/m² over 120 min, the FDR arm) on days 1 and 8 every 3 week cycle. In both treatment arms, carboplatin at AUC of 5 was administered over 4 h following gemcitabine on day 1 of each cycle. Results From November 2003 to June 2005, a total of 42 patients, in which 7 (17%) patients had stage III_B disease and 35 (83%) had stage IV disease, were enrolled into this study. All patients were included in efficacy and toxicity assessment. No patient had a complete response. Seven (33%) patients in the standard arm and 10 (48%) in the FDR arm had a partial response. The median time to progression and median overall survival time in the standard arm was 5.4 months (95% CI, 3.8–7 months) and 11.5 months (95% CI, 8.2–14.8 months), respectively, while in the FDR arm was 6.5 (95% CI, 4.4–8.6 months) months, 12.0 months (95% CI, 11.3–12.7 months), respectively. The most frequently reported grade 3 or 4 hematological toxicities were thrombocytopenia (38% patients in the standard arm and 43% in the FDR arm) and neutropenia (24% in the standard arm and 33% in the FDR arm). Although hematological toxicity occurred in a little higher percent of patients in the FDR arm than in the standard arm, there were no discernible differences by statistical analysis in both treatment arms (P > 0.05). And significant nonhematologic toxicities were infrequent and tolerable in both arms. No significant difference existed also (P > 0.05). Conclusion In this phase II study, gemcitabine in combination with carboplatin either at standard rate or fixed dose rate infusion was clinically effective and well tolerated in patients with advanced NSCLC.     

Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003.

PURPOSE: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells. We conducted a phase III clinical trial to determine whether the addition of tirapazamine to paclitaxel and carboplatin offered a survival advantage when used in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Of 396 patients registered, 367 eligible patients were randomly assigned to either arm 1 (n = 181), which consisted of treatment every 21 days with paclitaxel 225 mg/m2/3 h, carboplatin (area under the curve = 6), and tirapazamine 260 mg/m2 in cycle 1 (which was escalated, if tolerable, to 330 mg/m(2) in cycle 2), or arm 2 (n = 186), which consisted of paclitaxel and carboplatin as in arm 1 with no tirapazamine. RESULTS: Patient characteristics were similar between the two arms. There were no statistically significant differences in response rates, progression-free survival, or overall survival. Patients on arm 1 had significantly (P < .05) more abdominal cramps, fatigue, transient hearing loss, febrile neutropenia, hypotension, myalgias, and skin rash and were removed from treatment more often as a result of toxicity than patients in arm 2 (26% v 13%, respectively; P = .003). More than 40% of patients did not have the tirapazamine dose escalated, primarily because of toxicity. The trial was closed early after an interim analysis demonstrated that the projected 37.5% improvement in survival (8 v 11 months median survival) in arm 1 was unachievable (P = .003). CONCLUSION: The addition of tirapazamine to paclitaxel and carboplatin does not result in improved survival in advanced NSCLC compared with paclitaxel and carboplatin alone but substantially increases toxicity.